This application presents a program of patient-oriented research designed to support a mentoring and research plan carried out by David Flockhart MD, PhD. The applicant is a GCRC investigator, who has a substantial track record in funded and published, patient-oriented investigation and mentoring in his designated area of study: Clinical Pharmacogenetics. He has reached a stage of rapid and productive growth in his career, at which heavy clinical and administrative responsibilities threaten to undermine his productivity. This award should allow him to continue to focus on patient-oriented research in the area of cytochrome P450 pharmacogenetics and on the mentoring of junior clinical investigators. The candidate will continue and expand a multidisciplinary research program in the broad area of cytochrome P450 pharmacogenetics, focusing on two enzymes known to possess clear functional polymorphisms: CYP2D6 and CYP3A5, and one where more research is necessary: CYP2B6. Mentoring opportunities will derive from ongoing studies on the pharmacogenetics of the treatment of breast cancer, including studies designed to test the hypothesis that cytochrome P450 pharmacogenetics can be used to anticipate the effects of tamoxifen, as well as from studies in the areas of Aromatase inhibitors, HIV, Sickle Cell disease and Pediatric Oncology in which the applicant plays an active mentoring role. Dr. Flockhart is Director of the Division of Clinical Pharmacology at Indiana University, P.I. of a T-32 Clinical Pharmacology Training Grant and co-director of a fellowship in Pharmacogenomics, Ethics and Public Policy. As such, he is highly _ qualified to provide clinical research training in the area of clinical pharmacogenomics, and to mentor young clinical investigators. The Indiana University School of Medicine is an outstanding environment for patient- oriented research with a strong GCRC, a strong informatics infrastructure and a vigorous Center for Bioethics, all of which are committed, institutional supports for the candidate.